Adoptive T cell therapy, which involves the reinfusion of expanded populations of tumor-specific T cells that have been isolated or engineered ex vivo, has achieved dramatic antitumor responses in a subset of patients with advanced melanoma and leukemia. However, only small subsets of patients have benefited from adoptive T cell therapy, in part because of the difficulty identifying and expanding high avidity tumor-reactive T cells from patients, and of maintaining the number and anti-tumor activity of the T cells in the patient after adoptive transfer. The introduction of tumor-targeting receptors into T cells by gene transfer to confer tumor reactivity provides a promising approach to overcome the obstacle of having to isolate tumor-reactive T cells from each patient to treat their malignancy, but does not solve the problem that the duration of in vivo survival of antigen-specific T cells that have been numerically expanded by culture ex vivo and adoptively transferred to patients is unpredictable, and often short. Thus, the identification of characteristics of T cells that determine their capacity to persist after transfer, and strategies to enhance survival and/or to expand transferred T cells in vivo that can be applied to humans could improve therapeutic outcome. Studies supported by this grant have utilized a nonhuman primate (NHP) model to address this important impediment to adoptive T cell therapy. This work has identified heritable qualities of TE cells that determine their fate in vivo and ability to establish durable T cell memory, and identified a role for interleukin 15 (IL-15) for supporting the long-term persistence of transferred T cells. The techniques used in the NHP model recapitulate those used in human adoptive therapy, and findings from this model are being translated into clinical trials of T cell therapy for cancer. The studies in this competing renewal will utilize the model to optimize strategies for administering IL-15 and for vaccination with a cellular vaccine comprised of an activated T cell that displays the cognate antigen, to enhance the magnitude and durability of T cell immunity achieved by adoptive transfer of TE cells, and evaluate the safety of targeting a novel molecule that is selectively expressed on human B cell malignancies. These studies have been selected for their immediate relevance and potential for rapid translation to human adoptive T cell therapy. The specific aims are: 1. To determine the safety and efficacy of subcutaneous IL-15 for improving the survival of adoptively transferred TE cells and their conversion to memory cells. 2. To optimize the use of systemic vaccination with T-cell antigen presenting cells (T-APC) for driving the in vivo expansion of adoptively transferred TE cells. 3. To determine the safety of adoptively transferring TE cells genetically modified to express a chimeric antigen receptor specific for ROR1, a surface molecule expressed on human B-CLL and mantle cell lymphoma, and conserved in M. mullata. PUBLIC HEALTH RELEVANCE: Adoptive T cell therapy involves the isolation and expansion of immune cells that can recognize and kill cancer cells when infused into patients. This approach has shown dramatic efficacy in some patients, but methods to improve the survival and magnitude of the transferred T cell response are needed. We are using an animal model to determine characteristics of T cells that determine their fate, and to develop and test novel methods to extend the survival and expand adoptively transferred T cells in the body. The results of these studies are directly relevant for treatment of patients with cancer by adoptive T cell therapy.